Method and system for monitoring sleep

ABSTRACT

A method of monitoring sleep of a sleeping subject is disclosed. The method comprises determining a phase shift of input radiofrequency signals received from the subject during sleep relative to output radiofrequency signals transmitted to the subject during sleep, calculating cardiac output based on the phase shift, and using the cardiac output for identifying sleep apnea events.

RELATED APPLICATIONS

This Application is a National Phase of PCT Patent Application No.PCT/IL2008/000309 having International filing date of Mar. 6, 2008,which is a continuation-in-part of U.S. patent application Ser. No.11/889,395 filed on Aug. 13, 2007.

PCT Patent Application No. PCT/IL2008/000309 also claims the benefit ofU.S. Provisional Patent Application No. 60/905,313 filed on Mar. 7,2007.

The contents of the above Applications are all incorporated herein byreference.

FIELD AND BACKGROUND OF THE INVENTION

The present invention, in some embodiments thereof, relates to medicalapplication and, more particularly, but not exclusively, to a method andsystem for monitoring sleep.

Apnea is a Greek word meaning “without breath” which is used in theliterature to describe a condition of a temporary pause in breathing.Sleep apnea refers to the temporary cessation of breathing during sleep.Sleep apneas have been classified into three types: obstructive sleepapnea (OSA), central sleep apnea (CSA) and mixed sleep apnea (MSA). Thedifference between obstructive sleep apnea and central sleep apnea isthat in obstructive sleep apnea the breathing passageways are blocked,while in central sleep apnea the neural drive to respiratory muscles istransiently abolished but the passageways can still be open. In centralsleep apnea the lungs form a reservoir for air flow even though theindividual is not breathing.

Mixed sleep apnea consists of a central sleep apnea component and anobstructive sleep apnea component. In mixed sleep apnea, the obstructivecomponent typically follows the central component. The most common typeof sleep apnea is obstructive sleep apnea.

Also known are obstructive sleep hypopnea, which is a milder form ofobstructive apnea characterized by partial obstruction of the upperairway passages, and central sleep hypopnea, which is a milder form ofcentral sleep apnea characterized by shallow breathing while the upperairway are open.

An apnea event generally leads to a progressive-type asphyxia until theindividual is briefly aroused from the sleeping state, thereby restoringairway patency or respiratory muscles activity thereby restoring airflowto the lung. Consequently, sleep of individuals diagnosed with sleepapnea is fragmented and of poor quality.

Sleep apneas, particularly of the obstructive type, are recognized aslife-threatening conditions. Individuals with sleep apnea have anincreased risk of suffocating during sleep or during surgery requiringgeneral anesthesia.

Sleep apnea is diagnosed using a test called Polysomnography (PSG),which involves the patient sleeping in a sleep lab connected to variousmeasurement instruments. The test provides an Apnea/Hypopnea Index (AHI)which drives a diagnosis of sleep apnea along with severity.

When an individual is diagnosed with sleep apnea, the individual may beprescribed a therapeutic regime involving the use of a ContinuousPositive Airway Pressure (CPAP) device. The CPAP device works bydelivering a steady flow of air through a soft, pliable mask worn overthe individual's nose. The CPAP device essentially pressurizes thethroat of the individual thereby preventing the collapse of the softtissue and keeping the airways open and allowing the individual tobreathe uninterrupted during sleep.

For more severe cases of OSA, surgery such as laser assisted uvuloplastyis used to provide a partial treatment. Additional types of treatmentsare disclosed in U.S. Pat. Nos. 5,988,171, 6,250,307, 6,523,542,6,431,174 and 6,601,584.

SUMMARY OF THE INVENTION

According to an aspect of some embodiments of the present inventionthere is provided a method of monitoring sleep of a sleeping subjectusing output radiofrequency signals transmitted to the subject duringsleep and input radiofrequency signals received from the subject duringsleep. The method comprises determining a phase shift of the inputradiofrequency signals relative to the output radiofrequency signals,calculating cardiac output based on the phase shift, and using thecardiac output for identifying sleep apnea events.

According to an aspect of some embodiments of the present inventionthere is provided a method of monitoring sleep of a sleeping subject.The method comprises transmitting output radiofrequency signals to thesubject during sleep, receiving input radiofrequency signals from thesubject during sleep, and executing the method described above.

According to some embodiments of the present invention the methodfurther comprises supplementing the cardiac output with blood oxygencontent which can be measured, for example, via pulse oximetry. In theseembodiments, the identification of the sleep apnea events can be basedon the cardiac output and the blood oxygen content. For example, totaloxygen delivery can be estimated as further detailed hereinunder.

According to some embodiments of the present invention the methodfurther comprises estimating or receiving hemoglobin concentration ofthe sleeping subject. In some embodiments, the hemoglobin concentrationis used for estimating oxygen content.

According to some embodiments of the present invention the methodfurther comprises estimating total oxygen delivery and generating awakening signal when an estimated value is below a predeterminedthreshold.

According to some embodiments of the invention the identification of thesleep apnea events is further based on the estimated value of the totaloxygen delivery.

According to some embodiments of the present invention the methodfurther comprises controlling positive airway pressure delivered to thesubject based on the estimated value of the total oxygen delivery. Invarious exemplary embodiments of the invention the control of airwaypressure is in a closed loop feedback with the estimation of totaloxygen delivery. Thus, the method controls the delivered positive airwaypressure such as to ensure that the estimated amount of total oxygendelivery is above a predetermined threshold, or within a predeterminedrange.

According to some embodiments of the present invention the methodfurther comprises reducing or eliminating amplitude modulation of theinput radiofrequency signals so as to provide input radiofrequencysignals of substantially constant envelope.

According to some embodiments of the present invention the methodfurther comprises mixing the output radiofrequency signals and the inputradiofrequency signals so as to provide a mixed radiofrequency signal,and filtering out a portion of the mixed radiofrequency signal so as tosubstantially increase a signal-to-noise ratio of a remaining portion ofthe mixed radiofrequency signal.

According to some embodiments of the present invention the methodfurther comprises applying a dynamically variable filter.

According to an aspect of some embodiments of the present inventionthere is provided apparatus for monitoring sleep of a sleeping subjectusing output radiofrequency signals transmitted to the subject duringsleep and input radiofrequency signals received from the subject duringsleep. The apparatus comprises a phase shift determinator configured fordetermining a phase shift of the input radiofrequency signals relativeto the output radiofrequency signals, a cardiac output calculatorconfigured for calculating cardiac output based on the phase shift, anda sleep apnea identification unit configured for identifying sleep apneaevents based on the cardiac output.

According to an aspect of some embodiments of the present inventionthere is provided a system for monitoring sleep of a sleeping subject.The system comprises a radiofrequency generator for generating outputradiofrequency signals, a plurality of electrodes designed fortransmitting the output radiofrequency signals to the subject and forsensing input radiofrequency signals from the subject, and themonitoring apparatus described above.

According to some embodiments of the present invention the systemfurther comprises a blood oxygen measuring device, wherein the sleepapnea identification unit is configured to identify the sleep apneaevents based on the cardiac output and the blood oxygen content.

According to some embodiments of the present invention the apparatusfurther comprises a total oxygen delivery estimator configured forestimating total oxygen delivery.

According to some embodiments of the invention the sleep apneaidentification unit is configured to identify the sleep apnea eventsbased on an estimated value of the total oxygen delivery and the cardiacoutput.

According to some embodiments of the invention the system comprises arespiratory therapy device, such as, but not limited to, a continuouspositive airway pressure (CPAP) device.

According to some embodiments of the invention the apparatus comprises aclosed-loop control unit which receives the estimated value of totaloxygen delivery from the total oxygen delivery estimator and controlsthe pressure delivered by the respiratory therapy device based on theestimated value. In various exemplary embodiments of the invention theclosed-loop control unit controls the pressure to ensure that theestimated value of total oxygen delivery is above a predeterminedthreshold or within a predetermined range.

According to some embodiments of the present invention the apparatusfurther comprises an envelope elimination unit designed and configuredfor reducing or eliminating amplitude modulation of the inputradiofrequency signals so as to provide input radiofrequency signals ofsubstantially constant envelope.

According to some embodiments of the present invention the apparatusfurther comprises: a mixer configured for mixing the outputradiofrequency signals and the input radiofrequency signals, to providea mixed radiofrequency signal; and a radiofrequency filter for filteringout a portion of the mixed radiofrequency signal so as to substantiallyincrease a signal-to-noise ratio of a remaining portion of the mixedradiofrequency signal.

According to some embodiments of the present invention the apparatusfurther comprises a filtering unit configured for filtering the inputsignals using dynamically variable filter.

According to some embodiments of the present invention the cardiacoutput is calculated using a linear relationship between the phase shiftand the cardiac output.

According to some embodiments of the present invention the dynamicallyvariable filter is adapted in response to a change in a physiologicalcondition of the subject.

According to some embodiments of the invention the physiologicalcondition is a heart rate of the subject.

According to some embodiments of the invention a lower frequency boundcharacterizing the filter is about 0.9*(HR/60) Hz at all times, whereinthe HR is the heart rate in units of beats per minute.

According to some embodiments of the invention an upper frequency boundcharacterizing the filter is about 6+1.5*[(HR/60)−1] Hz at all times,wherein the HR is the heart rate in units of beats per minute.

Unless otherwise defined, all technical and/or scientific terms usedherein have the same meaning as commonly understood by one of ordinaryskill in the art to which the invention pertains. Although methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of embodiments of the invention, exemplarymethods and/or materials are described below. In case of conflict, thepatent specification, including definitions, will control. In addition,the materials, methods, and examples are illustrative only and are notintended to be necessarily limiting.

Implementation of the method and/or system of embodiments of theinvention can involve performing or completing selected tasks manually,automatically, or a combination thereof. Moreover, according to actualinstrumentation and equipment of embodiments of the method and/or systemof the invention, several selected tasks could be implemented byhardware, by software or by firmware or by a combination thereof usingan operating system.

For example, hardware for performing selected tasks according toembodiments of the invention could be implemented as a chip or acircuit. As software, selected tasks according to embodiments of theinvention could be implemented as a plurality of software instructionsbeing executed by a computer using any suitable operating system. In anexemplary embodiment of the invention, one or more tasks according toexemplary embodiments of method and/or system as described herein areperformed by a data processor, such as a computing platform forexecuting a plurality of instructions. Optionally, the data processorincludes a volatile memory for storing instructions and/or data and/or anon-volatile storage, for example, a magnetic hard-disk and/or removablemedia, for storing instructions and/or data. Optionally, a networkconnection is provided as well. A display and/or a user input devicesuch as a keyboard or mouse are optionally provided as well.

BRIEF DESCRIPTION OF THE DRAWINGS

Some embodiments of the invention are herein described, by way ofexample only, with reference to the accompanying drawings. With specificreference now to the drawings in detail, it is stressed that theparticulars shown are by way of example and for purposes of illustrativediscussion of embodiments of the invention. In this regard, thedescription taken with the drawings makes apparent to those skilled inthe art how embodiments of the invention may be practiced.

In the drawings:

FIG. 1 is a flowchart diagram of a method suitable for monitoring sleepof a sleeping subject according to various exemplary embodiments of thepresent invention;

FIG. 2 shows cardiac output response of a female subject during positiveend expiratory pressure treatment, as measured according to someembodiments of the present invention and further measured using apulmonary artery catheter;

FIG. 3 is a flowchart diagram of a more detailed method suitable formonitoring sleep according to various exemplary embodiments of thepresent invention;

FIGS. 4 a-b show a representative example of dynamically varyingfrequency bounds, employed according to embodiments of the presentinvention;

FIG. 4 c show a representative example of a dynamically varyingfrequency band, employed according to embodiments of the presentinvention;

FIG. 5 is a schematic illustration of apparatus for monitoring sleep,according to various exemplary embodiments of the present invention;

FIG. 6 is a schematic illustration of a signal processing unit,according to various exemplary embodiments of the present invention;

FIG. 7 is a block diagram of electronic circuitry, according to variousexemplary embodiments of the present invention; and

FIG. 8 is a schematic illustration of a system for monitoring sleep of asleeping subject.

DESCRIPTION OF SPECIFIC EMBODIMENTS OF THE INVENTION

The present invention, in some embodiments thereof, relates to medicalapplication and, more particularly, but not exclusively, to a method,apparatus and system for monitoring sleep.

Before explaining at least one embodiment of the invention in detail, itis to be understood that the invention is not necessarily limited in itsapplication to the details of construction and the arrangement of thecomponents and/or methods set forth in the following description and/orillustrated in the drawings and/or the Examples. The invention iscapable of other embodiments or of being practiced or carried out invarious ways.

Computer programs implementing the method according to embodiments ofthe present invention can commonly be distributed to users on adistribution medium such as, but not limited to, a floppy disk, CD-ROMand flash memory cards. From the distribution medium, the computerprograms can be copied to a hard disk or a similar intermediate storagemedium. The computer programs can be run by loading the computerinstructions either from their distribution medium or their intermediatestorage medium into the execution memory of the computer, configuringthe computer to act in accordance with the method of this invention. Allthese operations are well-known to those skilled in the art of computersystems.

The method, apparatus and system of the present embodiments areparticularly useful for the analysis of sleep. Yet, the use of thepresent embodiments in other situations, such as general anesthesia orthe like, is not excluded from the scope of the present invention.

The method, apparatus and system of the present embodiments are suitablefor identifying sleep apnea events caused by blockage or partialblockage of breathing passageways and/or by lack or reduced neural driveto the respiratory muscles.

The recurrent episodes of nocturnal asphyxia, cerebral hypoxia andarousal from sleep that characterize sleep apnea lead to a series ofsecondary physiologic events, which in turn give rise to variousclinical complications.

Some manifestations are neuropsychiatric and behavioral disturbancesthat generally arise from the fragmentation of sleep and loss ofslow-wave sleep induced by the recurrent arousal responses.Manifestations of neuropsychiatric and behavioral disturbances includeexcessive daytime sleepiness, intellectual impairment, memory loss,personality disturbances and impotence. Other manifestations arecardiorespiratory in nature and are thought to arise from the recurrentepisodes of nocturnal asphyxia. Cardiorespiratory manifestations includebradycardia followed by tachycardia, tachyarrhythmia.

Central sleep apnea may also lead to secondary physiological andclinical consequences. Central sleep apnea can be identified in a widespectrum of individuals with medical, neurological and/or neuromusculardisorders associated with diurnal alveolar hypoventilation or periodicbreathing. In less severe cases, central sleep apnea events particularlyoccur at sleep onset and in REM sleep. In clinically significant centralsleep apnea, events occur also in other sleep stages. Manifestations ofcentral sleep apnea may include alveolar hypoventilation syndrome,daytime hypercapnia, hypoxemia, recurrent respiratory failure,polycythemia, pulmonary hypertension and right-sided heart failure.

Chronic sleep apnea may lead to various serious complications such asheart failure. The mechanism by which sleep apnea patients develop heartfailure relates to build up of intrathoracic pressure. During an apneaevent the pressure in the chest builds due to deposition of carbondioxide in the lungs with no ventilation. The rising carbon dioxidepressure increases thoracic pressure and reduces the venous return tothe right heart resulting in a reduced or failure of left ventricularfunction. Increased left ventricular after load, recurrent nocturnalhypoxemia and elevated sympathoadrenal activity also contribute to thereduced left ventricular function.

It was found by the present inventors that apnea events can beidentified by monitoring cardiac output. Specifically, since a reducedleft ventricular filling is accompanied by a drop in cardiac output, anapnea event can be identified when the cardiac output is reduced.

Referring now to the drawings, FIG. 1 is a flowchart diagram of a methodsuitable for monitoring sleep of a sleeping subject according to variousexemplary embodiments of the present invention.

It is to be understood that, unless otherwise defined, the method stepsdescribed hereinbelow can be executed either contemporaneously orsequentially in many combinations or orders of execution. Specifically,the ordering of the flowcharts diagrams is not to be considered aslimiting. For example, two or more method steps, appearing in thefollowing description or in the flowchart diagrams in a particularorder, can be executed in a different order (e.g., a reverse order) orsubstantially contemporaneously. Additionally, several method stepsdescribed below are optional and may not be executed.

The method is particularly useful for monitoring sleep using outputradiofrequency signals transmitted to the subject during sleep and inputradiofrequency signals received from the subject during sleep.

The method begins at step 10 and continues to step 12 in which a phaseshift of the input radiofrequency signals relative to the outputradiofrequency signals is determined. The method continues to step 14 inwhich a cardiac output is calculated, based on the phase shift. Themethod continues to step 16 in which the cardiac output is used foridentifying sleep apnea events.

The method ends at step 18.

Before providing a further detailed description of the method andapparatus for monitoring sleep, as delineated hereinabove and inaccordance with some embodiments of the present invention, attentionwill be given to the advantages and potential applications offeredthereby.

The present inventors conducted experiments in which cardiac outputresponse to positive end expiratory pressure was evaluated. Withoutbeing bound to any theory, it is postulated that positive end expiratorypressure can be surrogate for sleep apnea because it creates positivethoracic pressure induced by mechanical ventilation in anesthetizedsubjects in intensive care units. The pressure dynamics in positive endexpiratory pressure are similar to those observed during an apneaepisode.

FIG. 2 shows cardiac output response of a female subject during positiveend expiratory pressure treatment in intensive care unit. The cardiacoutput was measured using a conventional pulmonary artery catheter(Swan-Ganz catheter), as well as non-invasively using the phase shift ofthe input relative to output radiofrequency signals according to variousembodiments of the present invention. Measurements performed accordingto the present embodiments are designated NICOM (Non-Invasive CardiacOutput Monitoring), and measurements performed using the pulmonaryartery catheter are designated SWANG. Onsets of positive end expiratorypressure are marked by dark rectangles.

As shown in FIG. 2, significant drops in cardiac output are correlatedwith the onset of positive end expiratory pressure. Thus, apnea eventscan be identified when the level of cardiac output is reduced.

In various exemplary embodiments of the invention an apnea event isidentified when the cardiac output as calculated using the phase shiftbetween the radiofrequency signals is reduced by at least 30%, morepreferably at least 40%, more preferably at least 50% over a time periodof less than two minutes. In embodiments in which arterial oxygensaturation (SPO₂) is monitored, a lower threshold of comprises reductioncan be employed. For example, an apnea event can be identified when thecalculated cardiac output is reduced by at least 25% and the value ofSPO₂ is significantly decreased (say, by more than 40%).

Traditionally, sleep apnea is diagnosed via PSG. The logistics and costof PSG, however significantly complicate the ability to diagnose thecondition. The present embodiments provide a screening modality whichcan be used in small facilities and at home. The present embodimentsallow fast screening of many subjects, by providing each subject with asystem operable to execute selected steps of the method describedherein. The present embodiments also allow screening out subjects forwhich sleep study is no required, thereby saving significant resources.

The present embodiments can also be employed by subjects who alreadybeen diagnosed with sleep apnea and for whom a CPAP device has beenprescribed. Specifically, the present embodiments can be used as asupplement to a conventional treatment (e.g., a CPAP device) so as toassess the efficacy of treatment. For example, the present embodimentscan be used for determining whether or not a sufficient amount of oxygenis delivered to vital organs such as the brain, heart and kidneys. It isrecognized that even when a CPAP device pushes air to the lungs, oxygendelivery from the cardiopulmonary system to vital tissues is notguaranteed. For example, a significant drop in cardiac output may resultin insufficient oxygen delivery even when the CPAP device increases theoxygen content in the blood. In this case, a system according to someembodiments of the present invention can signal the CPAP device toincrease the positive airway pressure and/or generate a wakening signalsensible by the sleeping subject.

A more detailed method for monitoring sleep according to someembodiments of the present invention is illustrated in the flowchartdiagram of FIG. 3.

The method begins at step 20 and optionally continues to step 22 inwhich output radiofrequency signals are transmitted to the subjectduring sleep, and step 24 in which input radiofrequency signals arereceived from the subject during sleep. The output radiofrequencysignals can be generated by a radiofrequency generator which generates aperiodic high frequency current output in response to a periodic controlinput signal. The current output can be transmitted to the subject viaan arrangement of electrodes for carrying current output from theradiofrequency generator as known in the art. The electrodes can beconnected to locations of the body of the subject, e.g., above and belowthe heart. Since the transmission and reception of signals is doneduring sleep, the electrodes are optionally and preferably placed on thesubject's back so as not to interfere with upper body motion.

Current, generated by the radiofrequency generator, flows across thethorax and causes a voltage drop due to the impedance of the body. Theinput radiofrequency signals are typically, but not obligatorily, relateto the hemodynamic reactance of an organ of the subject.

As used herein, “hemodynamic reactance” refers to the imaginary part ofthe impedance. Techniques for extracting the imaginary part from thetotal impedance are known in the art. Typically, such extraction isperformed at hardware level but the use of algorithm at a software levelis not excluded from the scope of the present invention.

According to some embodiments of the present invention the methodcontinues to step 26 in which amplitude modulation of the inputradiofrequency signals is reduces or, more preferably, eliminated.Optionally and preferably the phase modulation of the signals ismaintained. The input radiofrequency signals typically carry asubstantial amount of AM noise, which can be described, withoutlimitation as a signal ν(t)cos(ωt+φ(t)), which contains both phase andamplitude modulation. According to some embodiments the method generatessignals having a substantial constant envelope, e.g., ν₀ cos(ωt+φ(t)),where ν₀ is substantially a constant. The obtained signals thusrepresent the phase (or frequency) modulation of the inputradiofrequency signal. The reduction or elimination of the amplitudemodulation can be achieved, for example, using a limiter amplifier whichamplifies the radiofrequency signals and limits their amplitude suchthat the amplitude modulation is removed.

In some embodiments, the method proceeds to step 28 in which the outputradiofrequency signals are mixed with the input radiofrequency signalsso as to provide a mixed radiofrequency signal. According to a preferredembodiment of the present invention, the mixed radiofrequency signal iscomposed of a plurality of radiofrequency signals, which may be, in oneembodiment, a radiofrequency sum and a radiofrequency difference. A sumand a difference may be achieved, e.g., by multiplying the input andoutput signals. Since a multiplication between two frequencies isequivalent to a frequency sum and a frequency difference, the mix signalis composed of the desired radiofrequency sum and radiofrequencydifference.

One ordinarily skilled in the art would appreciate that the advantage inthe production of a radiofrequency sum and a radiofrequency differenceis that whereas the radiofrequency sum includes both the signal and aconsiderable amount of electrical noise, the radiofrequency differenceis approximately noise-free.

According to a preferred embodiment of the method continues to step 30in which a portion of the mixed signal is filtered out such that aremaining portion of the mixed signal is characterized by asignal-to-noise ratio (SNR) which is substantially higher compared tothe signal-to-noise ratio of the mixed signal or input radiofrequencysignal.

The method continues to step 32 in which a phase shift Δφ of the inputradiofrequency signals relative to the output radiofrequency signals isdetermined. It was found by the inventors of the present invention thatthe phase shift of the input signals, as received from the subject,relative to the output signals as generated by the radiofrequencygenerator, is indicative of the cardiac output of the subject.

The advantage of using Δφ for determining the cardiac output is that therelation between the blood flow and Δφ depends on fewermeasurement-dependent quantities as compared to conventionaldetermination techniques in which the impedance is used. The phase shiftcan be determined for any frequency component of the spectrum ofradiofrequency signals received from the organ. For example, in oneembodiment, the phase shift is preferably determined from the basefrequency component, in another embodiment the phase shift is preferablydetermined from the second frequency component, and so on. Alternativelythe phase shift can be determined using several frequency components,e.g., using an appropriate averaging algorithm.

In some embodiments of the present invention the method continues tostep 34 in which a dynamically variable filter is applied. Thedynamically variable filter filters the data according to a frequencyband which is dynamically adapted in response to a change in thephysiological condition of the subject. It was found by the Inventor ofthe present invention that the dynamical adaptation of the frequencyband to the physiological condition of the subject can significantlyreduce the influence of unrelated signals on the measured property.

Thus, in the present embodiment, step 34 includes a process in whichfirst the physiological condition of the subject is determined, then afrequency band is selected based on the physiological condition of thesubject, and thereafter the input signals are filtered according tofrequency band. The frequency band is dynamically adapted in response toa change in the physiological condition.

The physiological condition is preferably, but not obligatorily, theheart rate of the subject. The data pertaining to the physiologicalcondition can be collected via a suitable data collection unit either inanalog or digital form, as desired. For example, the physiologicalcondition can be a heart rate which can be determined, e.g., by analysisof ECG signals or the like.

While the embodiments below are described with a particular emphasis tophysiological condition which is a heart rate, it is to be understoodthat more detailed reference to the heart rate is not to be interpretedas limiting the scope of the invention in any way. For example, inexemplary embodiments of the present invention the physiologicalcondition is a ventilation rate of the subject, a repetition rate of aparticular muscle unit and/or one or more characteristics of an actionpotential sensed electromyography.

The adaptation of the frequency band to the physiological condition canbe according to any adaptation scheme known in the art. For example, oneor more parameters of the frequency band (e.g., lower bound, upperbound, bandwidth, central frequency) can be a linear function of aparameter characterizing the physiological condition. Such parameter canbe, for example, the number of heart beats per minute.

A representative example of a dynamically varying frequency bounds isillustrated in FIGS. 4 a-b. Shown in FIGS. 4 a-b is the functionaldependence of the frequency bounds (upper bound in FIG. 4 a and lowerbound in FIG. 4 b) on the heart rate of the subject. As shown in FIG. 4a, the upper bound of the frequency band varies linearly such that at aheart rate of about 60 beats per minute (bpm) the upper bound is about 6Hz, and at a heart rate of about 180 bpm the upper bound is about 9 Hz.Preferably, the upper bound is about 6+1.5×[(HR/60)−1] Hz at all times,where HR is the heart rate of the subject in units of bpm. As shown inFIG. 4 b, the lower bound of the frequency band varies linearly suchthat at a heart rate of about 60 the lower bound is about 0.9 Hz bpm andat a heart rate of about 180 bpm the lower bound is about 2.7 Hz. Thelower bound is about 0.9×(HR/60) Hz at all times.

As used herein the term “about” refers to ±10%.

A dynamically varying band pass filter (BPF) characterized by thefrequency bounds described above is illustrated in FIG. 4 c. As shown,each heart rate is associated with a frequency band defined by a lowerbound and an upper bound. For example, for a heart rate of 60 bpm, FIG.4 c depicts a BPF in which the lower bound is about 0.9 Hz and the upperbound is about 6 Hz.

It is to be understood that the values presented above and thefunctional relations illustrated in FIGS. 4 a-b are exemplaryembodiments and should not be considered as limiting the scope of thepresent invention in any way. In other exemplary embodiments, thefunctional relations between the frequency band and the physiologicalcondition can have different slopes and/or offsets, or they can benon-linear.

The method continues to step 36 in which the cardiac output iscalculated, based on Δφ. It was found by the inventor of the presentinvention that there is a linear relationship between Δφ and the cardiacoutput, with a proportion coefficient comprising the systolic ejectiontime, T. For example, the cardiac output CO can be calculated using therelation CO=const.×T×Δφ×HR, where HR is the heart rate of the subject(e.g., in units of beats per minutes), and “const.” is a constant whichcan be found, for example, using a calibration curve.

In some embodiments of the present invention, the method continues tostep 38 in which blood oxygen content is measured. This can be done, forexample, using a conventional non-invasive pulse oximeter, whichprovides an approximation of the saturation of oxyhemoglobin (SpO₂).Optionally, the method estimates or receives as input the hemoglobinconcentration of the sleeping subject, and uses the hemoglobinconcentration to estimate blood oxygen content. The blood oxygen contentcan be supplemented to the calculated cardiac output for the purpose ofimproving sensitivity and/or specificity. In some embodiments of thepresent invention the method continues to step 40 in which the totaloxygen delivery is estimated. The total oxygen delivery can be estimatedby combining the cardiac output, oxyhemoglobin saturation and hemoglobinconcentration. For example, total oxygen delivery rate (typicallyexpressed in units of mL of oxygen per minute) can be estimated bymultiplying the cardiac output by the oxygen content.

In some embodiments of the present invention the method continues tostep 42 in which positive airway pressure delivered to the subject iscontrolled, based on the estimated value of the total oxygen delivery.In various exemplary embodiments of the invention the control of airwaypressure is in a closed loop feedback with the estimation of totaloxygen delivery. Thus, the method controls the delivered positive airwaypressure such as to ensure that the estimated amount of total oxygendelivery rate is above a predetermined threshold, or within apredetermined range.

The method continues to step 44 in which the calculated cardiac outputis used for identifying sleep apnea events. Generally, sleep apneaevents correlate with a significantly fast drop in the cardiac output(see the non limiting example of FIG. 2). Thus, according to the apreferred embodiment of the present invention, when the cardiac outputis reduced by a predetermined percentage over a sufficiently short andpredetermined time period, the method identifies sleep apnea event. Invarious exemplary embodiments of the invention an apnea event isidentified when the cardiac output is reduced by at least 30%, morepreferably at least 40%, more preferably at least 50% over a time periodof less than two minutes. Upon identification of an apnea event themethod optionally generate a wakening signal (step 46).

When other quantities are measured and/or estimated, these quantitiesare optionally and preferably used together with the calculated cardiacoutput for identifying sleep apnea events. Addition of other quantitiesmay aid in reducing false positive and false negative identificationsolely based on cardiac output alone. For example, blood oxygen contentcan be supplemented to the cardiac output, wherein a sleep apnea eventcan be identified when there is a predetermined drop in cardiac outputand a predetermined drop in oxygen content.

When the total oxygen delivery is estimated by the method, the estimatedvalue can be used to identify apnea event and/or to asses subjectcondition. For example, when the total oxygen delivery falls below apredetermined threshold which can be expressed as percentage ofbaselines, the method can generate a wakening alarm sensible by thesleeping subject or control a CPAP device to increase pressure.

The method ends at step 48.

Reference is now made to FIG. 5 which is a schematic illustration ofapparatus 400 for monitoring sleep of a sleeping subject 121, accordingto various exemplary embodiments of the present invention.

Apparatus 400 comprises an input unit 142 for receiving inputradiofrequency signals sensed from the organ. The input radiofrequencysignals typically comprise radiofrequency signals related to theelectrical properties of the organ (e.g., bioimpedance which maygenerally relate to the impedance and/or hemodynamic reactance of theorgan). The signals are sensed from one or more sensing locations 408 onthe organ of subject 121 and are originated by output radiofrequencysignals 124 generated by a radiofrequency generator 122.

Apparatus 400 further comprises a signal processing unit 404 whichprocesses the input radiofrequency signals. The processing may include,for example, mixing, demodulation, determination of phase shift, analogfiltering, sampling and any combination thereof. Signal processing unit404 may or may not be in communication with radiofrequency generator122, as desired. A representative example of signal processing unit 404is provided hereinunder with reference to FIG. 6.

Apparatus 400 is optionally and preferably designed for determining aphase shift Δφ of signals 126 relative to signals 124. This can be doneusing a phase shift determinator 50 (not shown, see FIG. 6) which canoperate according to any known technique for determining a phase shift.The phase shift can be determined for any frequency component of thespectrum of radiofrequency signals received from the organ. For example,in one embodiment, the phase shift is determined from the base frequencycomponent, in another embodiment the phase shift is determined from thesecond frequency component, and so on. Alternatively the phase shift canbe determined using several frequency components, e.g., using anappropriate averaging algorithm.

The input radiofrequency signals may include one or more noisecomponents, which may be introduced into the signal due to variousreasons, e.g., subject agitation or breathing. In various exemplaryembodiments of the invention apparatus 400 is capable of reducing oreliminating these noise components. In some embodiments of the presentinvention apparatus 400 further comprises a filtering unit 406 whichfilters the processed input signals. Unit 406 preferably performs thefiltration operation in the frequency domain. Thus, in various exemplaryembodiments of the invention, a series of samples of the processedradiofrequency signals are transformed, e.g., by a Fast FourierTransform (FFT), to provide a spectral decomposition of the signals inthe frequency domain. The transformation to the frequency domain can bedone by a data processor. Algorithms for performing such transformationsare known to those skilled in the art of signal processing.

The obtained spectral decomposition of the signal is filtered by unit406 which typically eliminates one or more of the frequencies in thespectrum, depending on the upper and lower frequency bounds of thefilter employed by unit 406. Unit 406 preferably employs a dynamicallyvariable filter, such as, but not limited to, the dynamically variablefiler described hereinabove.

In some embodiments of the present invention apparatus 400 comprises acardiac output calculator 52 which calculates the cardiac output asfurther detailed hereinabove. Optionally, apparatus 400 comprises anestimator 54 which estimates total oxygen delivery as further detailedhereinabove. Estimator 54 can communicate with a blood oxygen measuringdevice (not shown, see FIG. 8) and receive oxygen data therefrom for thepurpose of performing the estimations. Estimator 54 can also receivehemoglobin concentration as input and use the hemoglobin concentrationin combination with data received from the blood oxygen measuring deviceto estimate the oxygen content. For example, when the blood oxygenmeasuring device provides saturation data, such as arterial oxygensaturation, the oxygen content can be estimated as the product ofarterial oxygen saturation, hemoglobin concentration and a constant,which reflects the hemoglobin-oxygen binding capacity.

A sleep apnea identification unit 56 uses the calculated cardiac outputand identifies sleep apnea events as further detailed hereinabove. Inembodiments in which estimator 54 is employed unit 56 optionally andpreferable uses the estimated quantity (oxygen content, total oxygendelivery) in combination with the calculated cardiac output foridentifying sleep apnea events. Unit 56 can also be configured toreceive oxygen content data from a blood oxygen measuring device or fromestimator 54 and use the oxygen content data in combination with thecalculated cardiac output for identifying sleep apnea events. Calculator52 and estimator 54 can be associated with a data processor 142. Dataprocessor 142 can also be employed by unit 406 for performing thetransformation to the frequency domain and/or eliminating the frequencycomponents according to the dynamically variable frequency bounds.

Data processor 142 can also be configured for calculating otherquantities, e.g., stroke volume and/or other blood-volume relatedquantities.

Optionally, apparatus 400 comprises a closed-loop control unit 144 whichreceives the estimated value of total oxygen delivery from estimator 54and controls pressure delivered by a respiratory therapy device (notshown, see FIG. 8) based on the estimated value. In various exemplaryembodiments of the invention closed-loop control unit 144 controls thepressure to ensure that the estimated value of total oxygen delivery isabove a predetermined threshold or within a predetermined range.

Reference is now made to FIG. 6 which schematically illustrates signalprocessing unit 404, according to various exemplary embodiments of thepresent invention. Unit 404 preferably comprises a mixer 128,electrically communicating with generator 122, for mixing output signals124 and input signals 126, so as to provide a mixed radiofrequencysignal. Signals 124 and 126 may be inputted into mixer 128 through morethan one channel, depending on optional analog processing procedures(e.g., amplification) which may be performed prior to the mixing.

Mixer 128 may be any known radiofrequency mixer, such as, but notlimited to, double-balanced radiofrequency mixer and unbalancedradiofrequency mixer. According to a preferred embodiment of the presentinvention, the mixed radiofrequency signal is composed of a plurality ofradiofrequency signals, which may be, in one embodiment, aradiofrequency sum and a radiofrequency difference. A sum and adifference may be achieved, e.g., by selecting mixer 128 such thatsignals 124 and signals 126 are multiplied thereby. Since amultiplication between two frequencies is equivalent to a frequency sumand a frequency difference, mixer 128 outputs a signal which is composedof the desired radiofrequency sum and radiofrequency difference.

According to various exemplary embodiments of the present invention unit404 further comprises a phase shift determinator 50 for determining thephase shift of the input signals relative to the output signal. Phaseshift determinator 50 can determine the phase shift according to anytechnique known in the art. For example, the phase shift can bedetermined from the radiofrequency difference outputted from mixer 128.

According to a preferred embodiment of the present invention processingunit 404 further comprises electronic circuitry 132, which filters out aportion of the signal such that a remaining portion of the signal ischaracterized by a substantially increased signal-to-noise ratio.

Circuitry 132 is better illustrated in FIG. 7. According to anembodiment of the present invention circuitry 132 comprises a low passfilter 134 to filter out the high frequency content of the signal. Lowpass filter 134 is particularly useful in the embodiment in which mixer128 outputs a sum and a difference, in which case low pass filter 134filters out the radiofrequency sum and leaves the approximatelynoise-free radiofrequency difference. Low pass filter 134 may bedesigned and constructed in accordance with the radiofrequencydifference of a particular system which employs apparatus 400. Ajudicious design of filter 134 substantially reduces the noise contentof the remaining portion.

Circuitry 132 preferably comprises an analog amplification circuit 136for amplifying the remaining portion of the signal. The construction anddesign of analog amplification circuit 136 is not limited, providedcircuit 136 is capable of amplifying the signal. Amplification circuitssuitable for the present embodiments are found in International PatentApplication, Publication Nos. WO 2004/098376 and WO 2006/087696 thecontents of which are hereby incorporated by reference.

According to a preferred embodiment of the present invention circuitry132 further comprises a digitizer 138 for digitizing the signal. Thedigitization of the signal is useful for further digital processing ofthe digitized signal, e.g., by a microprocessor.

Optionally, circuitry comprises a differentiator 140 (either a digitaldifferentiator or an analog differentiator) for performing at least onetime-differentiation of the measured impedance to obtain a respectivederivative (e.g., a first derivative, a second derivative, etc.) of thebioimpedance or hemodynamic reactance. Differentiator 140 may compriseany known electronic functionality (e.g., a chip) that is capable ofperforming analog or digital differentiation.

According to a preferred embodiment of the present invention signalprocessing unit 404 comprises an envelope elimination unit 135 whichreduces or, more preferably, eliminates amplitude modulation of signals126. Optionally and preferably, unit 135 maintains the phase modulationof signals 126. The output of unit 135 represents the phase (orfrequency) modulation of signal 126, as further detailed hereinabove.Unit 135 can employ, for example, a limiter amplifier which amplifiessignals 126 and limits their amplitude such that the amplitudemodulation is removed. The advantage of the removal of the amplitudemodulation is that it allows a better determination of the phase shiftΔφ between the input and output signals, as further detailedhereinabove.

Reference is now made to FIG. 8, which is a schematic illustration ofsystem 120 for monitoring sleep of a subject, according to a preferredembodiment of the present invention. System 120 preferably comprises aradiofrequency generator 122, for generating output radiofrequencysignals. Generator 122 may be embodied as any radiofrequency generator.System 120 further comprises a plurality of electrodes 125, which areconnected to the skin of subject 121. Electrodes 125 transmit outputradiofrequency signals 124, generated by generator 122 and sense inputradiofrequency signals 126 originated from the organ of subject 121.

System 120 preferably comprises any of the components of apparatus 400described above. According to a preferred embodiment of the presentinvention system 120 further comprises a detector 129 for detecting avoltage drop on a portion of the body of subject 121 defined by thepositions of electrodes 125. In response to the detected voltage,detector 129 preferably generates signals which are indicative ofimpedance of the respective portion of the body. In this embodiment, thestroke volume can be calculated using (dX/dt)_(max), as further detailedhereinabove. Knowing the stroke volume, the cardiac output is calculatedby multiplying the stroke volume by the heart rate of the subject. Morepreferably, detector 129 generates signals which are indicative of ahemodynamic reactance, X.

In some embodiments, system 120 comprises a blood oxygen measuringdevice 150 which provides apparatus 400 with oxygen data via acommunication line 152. Device 150 can be, for example, a conventionalpulse oximeter or the like. Apparatus 400 combines the calculatedcardiac output with the oxygen content data for identifying sleep apneaas further detailed hereinabove. The system In some embodiments of thepresent invention can comprise a display for displaying status of sleep(e.g., continually showing cardiac output and/or total oxygen delivery).The system can also comprise an alarm device for generating a wakeningsignal. The alarm preferably communicates with apparatus 400 whichsignals the alarm to generate the awakening signal upon occurrence of asleep apnea event or when the total oxygen delivery is below apredetermined threshold.

System 120 can also comprise a respiratory therapy device 154, such as,but not limited to, a continuous positive airway pressure (CPAP) device.Device 154 can comprise a blower connected through a hose and a mask,such as a nasal mask or a nasal cannula, to the patient's respiratoryairway. Device 54 can also include an air flow sensor and an airpressure sensor. Device 154 can be controlled by apparatus 400 (e.g.,via the closed-loop control unit 144, see FIG. 5) so as to ensure thatthe estimated oxygen delivery rate is above a predetermined threshold orwithin a predetermined range. Thus, a closed loop feedback can beestablished so as to continuously monitor the oxygen delivery asestimated by apparatus 400 and the pressure of air flow delivered bydevice 154, and to vary the pressure to accord with the estimated oxygendelivery.

Following are technical preferred values which may be used for selectivesteps and parts of the embodiments described above.

The output radiofrequency signals are preferably from about 10 KHz toabout 200 KHz in frequency and from about 10 mV to about 200 mV inmagnitude; the input radiofrequency signals are preferably about 75 KHzin frequency and about 20 mV in magnitude; a typical impedance which canbe measured by the present embodiments is from about 5 Ohms to about 75Ohms; the resulting signal-to-noise ratio of the present embodiments isat least 40 dB; low pass filter 134 is preferably characterized by acutoff frequency of about 35 Hz and digitizer 138 preferably samples thesignals at a rate of about 500-1000 samples per second.

The terms “comprises”, “comprising”, “includes”, “including”, “having”and their conjugates mean “including but not limited to”.

The term “consisting of means “including and limited to”.

The term “consisting essentially of” means that the composition, methodor structure may include additional ingredients, steps and/or parts, butonly if the additional ingredients, steps and/or parts do not materiallyalter the basic and novel characteristics of the claimed composition,method or structure.

As used herein, the singular form “a”, “an” and “the” include pluralreferences unless the context clearly dictates otherwise. For example,the term “a compound” or “at least one compound” may include a pluralityof compounds, including mixtures thereof.

Throughout this application, various embodiments of this invention maybe presented in a range format. It should be understood that thedescription in range format is merely for convenience and brevity andshould not be construed as an inflexible limitation on the scope of theinvention. Accordingly, the description of a range should be consideredto have specifically disclosed all the possible subranges as well asindividual numerical values within that range. For example, descriptionof a range such as from 1 to 6 should be considered to have specificallydisclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numberswithin that range, for example, 1, 2, 3, 4, 5, and 6. This appliesregardless of the breadth of the range.

Whenever a numerical range is indicated herein, it is meant to includeany cited numeral (fractional or integral) within the indicated range.The phrases “ranging/ranges between” a first indicate number and asecond indicate number and “ranging/ranges from” a first indicate number“to” a second indicate number are used herein interchangeably and aremeant to include the first and second indicated numbers and all thefractional and integral numerals therebetween.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination or as suitable in any other describedembodiment of the invention. Certain features described in the contextof various embodiments are not to be considered essential features ofthose embodiments, unless the embodiment is inoperative without thoseelements.

Although the invention has been described in conjunction with specificembodiments thereof, it is evident that many alternatives, modificationsand variations will be apparent to those skilled in the art.Accordingly, it is intended to embrace all such alternatives,modifications and variations that fall within the spirit and broad scopeof the appended claims.

All publications, patents and patent applications mentioned in thisspecification are herein incorporated in their entirety by referenceinto the specification, to the same extent as if each individualpublication, patent or patent application was specifically andindividually indicated to be incorporated herein by reference. Inaddition, citation or identification of any reference in thisapplication shall not be construed as an admission that such referenceis available as prior art to the present invention. To the extent thatsection headings are used, they should not be construed as necessarilylimiting.

What is claimed is:
 1. A method of monitoring sleep of a sleepingsubject using output radiofrequency signals transmitted to the subjectduring sleep and input radiofrequency signals received from the subjectduring sleep, the method comprising: determining a phase shift of theinput radiofrequency signals relative to the output radiofrequencysignals to provide processed signals; applying to said processed signalsa dynamically variable filter characterized by a frequency band which isdynamically adapted in response to a change in a physiological conditionof the subject; using a cardiac output calculator, calculating cardiacoutput based on said filtered processed signals; and using said cardiacoutput for identifying sleep apnea events.
 2. The method of claim 1,further comprising supplementing said cardiac output with blood oxygencontent, wherein said identification of said sleep apnea events is basedon said cardiac output and said blood oxygen content.
 3. The method ofclaim 1, further comprising inputting or estimating hemoglobinconcentration of the sleeping subject, wherein said identification ofsaid sleep apnea events is based on said cardiac output and saidhemoglobin concentration.
 4. The method of claim 3, further comprisingestimating total oxygen delivery and generating a wakening signal whenan estimated value is below a predetermined threshold.
 5. The method ofclaim 4, wherein said identification of said sleep apnea events isfurther based on said estimated value of said total oxygen delivery. 6.The method of claim 4, further comprising controlling positive airwaypressure delivered to the sleeping subject based on said estimatedvalue.
 7. The method of claim 1, further comprising reducing oreliminating amplitude modulation of said input radiofrequency signals soas to provide input radiofrequency signals of substantially constantenvelope.
 8. The method of claim 1, further comprising mixing saidoutput radiofrequency signals and said input radiofrequency signals soas to provide a mixed radiofrequency signal, and filtering out a portionof said mixed radiofrequency signal so as to substantially increase asignal-to-noise ratio of a remaining portion of said mixedradiofrequency signal.
 9. The method of claim 1, wherein said cardiacoutput is calculated using a linear relationship between said filteredprocessed signals and said cardiac output.
 10. The method of claim 1,wherein said physiological condition is a heart rate of the subject. 11.The method of claim 10, wherein a lower frequency bound characterizingsaid filter is about 0.9*(HR/60) Hz at all times, wherein said HR issaid heart rate in units of beats per minute.
 12. The method of claim10, wherein an upper frequency bound characterizing said filter is about6+1.5*[(HR/60)−1] Hz at all times, wherein said HR is said heart rate inunits of beats per minute.
 13. A method of monitoring sleep of asleeping subject, comprising: transmitting output radiofrequency signalsto the subject during sleep; receiving input radiofrequency signals fromthe subject during sleep; and executing the method of claim
 1. 14. Themethod of claim 13, further comprising measuring blood oxygen contentand supplementing said cardiac output with blood oxygen content, whereinsaid identification of said sleep apnea events is based on said cardiacoutput and said blood oxygen content.
 15. Apparatus for monitoring sleepof a sleeping subject using output radiofrequency signals transmitted tothe subject during sleep and input radiofrequency signals received fromthe subject during sleep, the apparatus comprising: a phase shiftdeterminator configured for determining a phase shift of the inputradiofrequency signals relative to the output radiofrequency signals, toprovide processed signals; a filtering unit configured for applying tosaid processed signals a dynamically variable filter characterized by afrequency band which is dynamically adapted in response to a change in aphysiological condition of the subject; a cardiac output calculatorconfigured for calculating cardiac output based on said filteredprocessed signals; and a sleep apnea identification unit configured foridentifying sleep apnea events based on said cardiac output.
 16. Theapparatus of claim 15, wherein the apparatus further comprises a totaloxygen delivery estimator configured for estimating total oxygendelivery.
 17. The apparatus of claim 16, wherein said sleep apneaidentification unit is configured to identify said sleep apnea eventsbased on an estimated value of said total oxygen delivery and saidcardiac output.
 18. The apparatus of claim 16, wherein the apparatusfurther comprises a closed-loop control unit configured for receiving anestimated value of said total oxygen delivery and controlling pressuredelivered by a respiratory therapy device based on said estimated value.19. The apparatus of claim 15, wherein the apparatus further comprisesan envelope elimination unit designed and configured for reducing oreliminating amplitude modulation of said input radiofrequency signals soas to provide input radiofrequency signals of substantially constantenvelope.
 20. The apparatus of claim 15, wherein the apparatus furthercomprises: a mixer configured for mixing said output radiofrequencysignals and said input radiofrequency signals, to provide a mixedradiofrequency signal; and a radiofrequency filter for filtering out aportion of said mixed radiofrequency signal so as to substantiallyincrease a signal-to-noise ratio of a remaining portion of said mixedradiofrequency signal.
 21. The apparatus of claim 15, wherein a lowerfrequency bound characterizing said filter is about 0.9*(HR/60) Hz atall times, wherein said HR is said heart rate in units of beats perminute.
 22. The apparatus of claim 15, wherein an upper frequency boundcharacterizing said filter is about 6+1.5*[(HR/60)−1] Hz at all times,wherein said HR is said heart rate in units of beats per minute.
 23. Asystem for monitoring sleep of a sleeping subject, comprising: aradiofrequency generator for generating output radiofrequency signals; aplurality of electrodes designed for transmitting said outputradiofrequency signals to the subject and for sensing inputradiofrequency signals from the subject; and the apparatus of claim 15.24. The system of claim 23, further comprising a blood oxygen measuringdevice.
 25. The system of claim 23, wherein the apparatus furthercomprises a total oxygen delivery estimator configured for estimatingtotal oxygen delivery, and wherein the apparatus further comprises aclosed-loop control unit configured for receiving an estimated value ofsaid total oxygen delivery and controlling pressure delivered by arespiratory therapy device based on said estimated value.
 26. The systemof claim 25, further comprising said respiratory therapy device.